Inflammatory bowel disorders (IBDs) are characterized by the inflammation of the intestine. Two prevalent forms of the disease are Crohn's disease and Ulcerative Colitis (“UC”). There have been three postulations as to the occurrence of the disorder. They are: reaction to an existent infection in the intestine; defective barrier between mucosa and luminal antigens; and/or a disoriented immune response system by the host's defense mechanism.
All these cases present inflammatory cascade reactions which lead to inflammation in the intestine. The disease instigates a series of steps which start with the breach of the barrier between the intestine and infectious agents. The damaged wall bridges the gulf and exposes the lamina propria immune cells to the internal bacteria and its products. Tissue injury results as the soluble products of activated inflammatory cells come into contact with the bacteria. Therapy to cure and control the disease is preferably designed to block the pro-inflammatory mediators at the end of the cascade as this would decrease the current drift of luminal bacteria and stabilize the immune response.
With specific discussion regarding the colon, the colon is one of the most important portions of the digestive system; in most vertebrates the colon is the last portion of the digestive system. In mammals the colon consists of four parts namely ascending colon, descending colon, transverse colon and the sigmoid colon. The cecum is present at the beginning of the ascending colon and is at an intersection of small and the large intestine. The contents of the large intestine are liquids but they change into solid form as they reach the rectum. The most important functions of the colon are maintaining the water balance absorbing certain vitamins especially vitamin K which is vital for clotting of blood, storing waste and reclaiming water.
As the chyme is processed in the small intestine, 90% of almost all of the nutrients and water are absorbed by the time it reaches the large intestine. As the chyme enters the large intestine the remaining water is absorbed and the chyme is combined with mucus and bacteria and forms the stool. Ulcerative colitis is an inflammatory disorder effecting the mucosa and sub-mucosa of the colon. Ulcerative colitis is one of the chronic inflammatory bowel diseases along with Crohn's disease, Diversion Colitis, Segmental Colitis, Collagenous and Lymphocytic Colitis.
Inflammation is mostly observed in the mucosa and the sub-mucosa. Epithelial cell degeneration is often observed in the tip of the intestinal crypt; the crypt abscess is the initial lesion in UC. This occurs due to the polymorphonuclear leukocytes accumulation within the intestinal crypt tip, the epithelial crypt cells die and chronic inflammatory cells including the neutrophils enter the crypt. The dismemberment of the colon decreases the fluid exchange on its surface leading to abnormal electrolyte absorption, hence creating loose stools. As a result of the inflammation, the vessels of the mucosa and sub-mucosa enlarge and tissue granules develop in the ulcerated part of the intestine, as part of the repair mechanism. The ulcerations destroy the mucosa in highly vascular sections leading to bleeding in the gut lumen. In the next phase, the repair mechanism continues to fill the ulcerations with granulated tissue, which leads to collagen being deposited in the lamina propria, which lead to formation of pseudopolyps as an expression of the granulated tissue causing clinical bowel obstruction.
There are various therapies for UC and Colitis. Sulfasalazine, or Corticosteroids, have been the common form of therapy for the disease for a period of time. Immunosuppressive drugs like 6-mercaptopurine and azathioprine are currently being used in higher number of cases for both active and remittent forms of the disease. Sulfasalazine consists of a sulfapyridine linked to 5-ASA through an azo bond. The drug, after being ingested orally, enters the system and less than ⅓ of the drug is absorbed from the jejunum, a portion of which is excreted through the urine un-metabolized.
The remaining of the un-absorbed portion remains in the small bowel as it is excreted through the bile. The drug moves through the intestine and interacts with the bacterial flora and to a small extent with the distal small intestine and in very little quantities in the colon. The bacteria in the colon cleave the azo bond separating Sulfasalazine, 5-ASA and Sulfapyridine. The sulfapyridine is metabolized by the liver after being absorbed from the colon and is later excreted through the urine. 5-ASA is minimally absorbed from the colon and remains in contact with colonic mucosa and is excreted through the feces. If any of these are taken as single agents without Sulfasalazine, they are absorbed in the jejunum and are excreted and typically do not reach the distal bowel site. As 5-ASA is the only segment reaching the distal colon, it is the active moiety causing the therapy; hence a new class of drugs called aminosalicylates came into play.
5-ASA, which is the active moiety of Sulfasalazine, inhibits both the proliferation of T cells and the production of processed antigens to the T cells. Both 5-ASA and Sulfasalazine inhibit T cells and natural killer cytotoxic effective cells. They also impair addition, chemotaxis, block Interleukin-1 production and of pro-inflammatory cytokines like Tumor Necrosis Factor. Both the compounds 5-ASA and Sulfasalazine inhibit production of cyclooxygenase, prostaglandin, 5-lipoxygenase and 5-lipoxygenase activating protein. Both the agents inhibit the initiation of nuclear factor-KB that plays an important role in activation and increased expression of genes for most of the pro-inflammatory cytokines, chemokines, addition molecules and inflammatory initiators. All of these are crucial perpetrators of development and progress of inflammatory bowel diseases.
There are some current strategies for the prevention and control of the disease, including, but not limited to, Rapidly Metabolizing Steroids, Bismuth Enema, and Probiotics.